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| | ==Crystal structure of the Nco-A1 PAS-B domain with YL-2== | | ==Crystal structure of the Nco-A1 PAS-B domain with YL-2== |
| - | <StructureSection load='5y7w' size='340' side='right' caption='[[5y7w]], [[Resolution|resolution]] 2.25Å' scene=''> | + | <StructureSection load='5y7w' size='340' side='right'caption='[[5y7w]], [[Resolution|resolution]] 2.25Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5y7w]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5Y7W OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5Y7W FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5y7w]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5Y7W OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5Y7W FirstGlance]. <br> |
| - | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ALC:2-AMINO-3-CYCLOHEXYL-PROPIONIC+ACID'>ALC</scene>, <scene name='pdbligand=MK8:2-METHYL-L-NORLEUCINE'>MK8</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.25Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Ncoa1, Src1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ALC:2-AMINO-3-CYCLOHEXYL-PROPIONIC+ACID'>ALC</scene>, <scene name='pdbligand=MK8:2-METHYL-L-NORLEUCINE'>MK8</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Histone_acetyltransferase Histone acetyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.48 2.3.1.48] </span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5y7w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5y7w OCA], [https://pdbe.org/5y7w PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5y7w RCSB], [https://www.ebi.ac.uk/pdbsum/5y7w PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5y7w ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5y7w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5y7w OCA], [http://pdbe.org/5y7w PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5y7w RCSB], [http://www.ebi.ac.uk/pdbsum/5y7w PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5y7w ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/NCOA1_MOUSE NCOA1_MOUSE]] Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion. Involved in the coactivation of different nuclear receptors, such as for steroids (PGR, GR and ER), retinoids (RXRs), thyroid hormone (TRs) and prostanoids (PPARs). Also involved in coactivation mediated by STAT3, STAT5A, STAT5B and STAT6 transcription factors. Displays histone acetyltransferase activity toward H3 and H4; the relevance of such activity remains however unclear. Plays a central role in creating multisubunit coactivator complexes that act via remodeling of chromatin, and possibly acts by participating in both chromatin remodeling and recruitment of general transcription factors. Required with NCOA2 to control energy balance between white and brown adipose tissues. Required for mediating steroid hormone response. Isoform 2 has a higher thyroid hormone-dependent transactivation activity than isoform 1 and isoform 3.<ref>PMID:8616895</ref> <ref>PMID:9506940</ref> <ref>PMID:12507421</ref> <ref>PMID:16148126</ref> | + | [https://www.uniprot.org/uniprot/NCOA1_MOUSE NCOA1_MOUSE] Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion. Involved in the coactivation of different nuclear receptors, such as for steroids (PGR, GR and ER), retinoids (RXRs), thyroid hormone (TRs) and prostanoids (PPARs). Also involved in coactivation mediated by STAT3, STAT5A, STAT5B and STAT6 transcription factors. Displays histone acetyltransferase activity toward H3 and H4; the relevance of such activity remains however unclear. Plays a central role in creating multisubunit coactivator complexes that act via remodeling of chromatin, and possibly acts by participating in both chromatin remodeling and recruitment of general transcription factors. Required with NCOA2 to control energy balance between white and brown adipose tissues. Required for mediating steroid hormone response. Isoform 2 has a higher thyroid hormone-dependent transactivation activity than isoform 1 and isoform 3.<ref>PMID:8616895</ref> <ref>PMID:9506940</ref> <ref>PMID:12507421</ref> <ref>PMID:16148126</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5y7w" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5y7w" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Nuclear receptor coactivator|Nuclear receptor coactivator]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Histone acetyltransferase]] | + | [[Category: Large Structures]] |
| - | [[Category: Lk3 transgenic mice]] | + | [[Category: Mus musculus]] |
| - | [[Category: Bae, J H]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Lee, J H]] | + | [[Category: Bae JH]] |
| - | [[Category: Lee, Y J]] | + | [[Category: Lee JH]] |
| - | [[Category: Lim, H S]] | + | [[Category: Lee YJ]] |
| - | [[Category: Song, J Y]] | + | [[Category: Lim HS]] |
| - | [[Category: Yoon, H S]] | + | [[Category: Song JY]] |
| - | [[Category: Inflammatory allergic diseases and cancer]] | + | [[Category: Yoon HS]] |
| - | [[Category: Nuclear receptor coactivator 1]]
| + | |
| - | [[Category: Stapled peptide]]
| + | |
| - | [[Category: Transcription-inihibitor complex]]
| + | |
| Structural highlights
Function
NCOA1_MOUSE Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion. Involved in the coactivation of different nuclear receptors, such as for steroids (PGR, GR and ER), retinoids (RXRs), thyroid hormone (TRs) and prostanoids (PPARs). Also involved in coactivation mediated by STAT3, STAT5A, STAT5B and STAT6 transcription factors. Displays histone acetyltransferase activity toward H3 and H4; the relevance of such activity remains however unclear. Plays a central role in creating multisubunit coactivator complexes that act via remodeling of chromatin, and possibly acts by participating in both chromatin remodeling and recruitment of general transcription factors. Required with NCOA2 to control energy balance between white and brown adipose tissues. Required for mediating steroid hormone response. Isoform 2 has a higher thyroid hormone-dependent transactivation activity than isoform 1 and isoform 3.[1] [2] [3] [4]
Publication Abstract from PubMed
The complex formation between transcription factors (TFs) and coactivator proteins is required for transcriptional activity, and thus disruption of aberrantly activated TF/coactivator interactions could be an attractive therapeutic strategy. However, modulation of such protein-protein interactions (PPIs) has proven challenging. Here we report a cell-permeable, proteolytically stable, stapled helical peptide directly targeting nuclear receptor coactivator 1 (NCOA1), a coactivator required for the transcriptional activity of signal transducer and activator of transcription 6 (STAT6). We demonstrate that this stapled peptide disrupts the NCOA1/STAT6 complex, thereby repressing STAT6-mediated transcription. Furthermore, we solved the first crystal structure of a stapled peptide in complex with NCOA1. The stapled peptide therefore represents an invaluable chemical probe for understanding the precise role of the NCOA1/STAT6 interaction and an excellent starting point for the development of a novel class of therapeutic agents.
Targeted Inhibition of the NCOA1/STAT6 Protein-Protein Interaction.,Lee Y, Yoon H, Hwang SM, Shin MK, Lee JH, Oh M, Im SH, Song J, Lim HS J Am Chem Soc. 2017 Nov 1. doi: 10.1021/jacs.7b08972. PMID:29090910[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kamei Y, Xu L, Heinzel T, Torchia J, Kurokawa R, Gloss B, Lin SC, Heyman RA, Rose DW, Glass CK, Rosenfeld MG. A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell. 1996 May 3;85(3):403-14. PMID:8616895
- ↑ Xu J, Qiu Y, DeMayo FJ, Tsai SY, Tsai MJ, O'Malley BW. Partial hormone resistance in mice with disruption of the steroid receptor coactivator-1 (SRC-1) gene. Science. 1998 Mar 20;279(5358):1922-5. PMID:9506940
- ↑ Picard F, Gehin M, Annicotte J, Rocchi S, Champy MF, O'Malley BW, Chambon P, Auwerx J. SRC-1 and TIF2 control energy balance between white and brown adipose tissues. Cell. 2002 Dec 27;111(7):931-41. PMID:12507421
- ↑ Xie H, Sadim MS, Sun Z. RORgammat recruits steroid receptor coactivators to ensure thymocyte survival. J Immunol. 2005 Sep 15;175(6):3800-9. PMID:16148126
- ↑ Lee Y, Yoon H, Hwang SM, Shin MK, Lee JH, Oh M, Im SH, Song J, Lim HS. Targeted Inhibition of the NCOA1/STAT6 Protein-Protein Interaction. J Am Chem Soc. 2017 Nov 1. doi: 10.1021/jacs.7b08972. PMID:29090910 doi:http://dx.doi.org/10.1021/jacs.7b08972
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